Parkinson disease (PD) is a devastating, largely nonfamilial, age-related disorder caused by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Release of DA from these neurons into the dorsal striatum is crucial for regulating movement and their loss causes PD. Unfortunately, the mechanisms underlying SNc neurodegeneration remain unclear, and currently there is no cure for PD, only symptomatic treatments. Recently, several regulator of G protein signaling (RGS) proteins have emerged as critical modulators of PD pathogenesis and/or motor dysfunction and dyskinesia: RGSs 4, 6, 9, and 10. Striatal RGS4 has been shown to exacerbate motor symptoms of DA loss by suppressing M₄-autoreceptor-Gα_i/o signaling in striatal cholinergic interneurons. RGS6 and RGS9 are key regulators of D₂R-Gα_i/o signaling in SNc DA neurons and striatal medium spiny neurons, respectively. RGS6, expressed in human and mouse SNc DA neurons, suppresses characteristic PD hallmarks in aged mice, including SNc DA neuron loss, motor deficits, and α-synuclein accumulation. After DA depletion, RGS9 (through its inhibition of medium spiny neuron D₂R signaling) suppresses motor dysfunction induced by L-DOPA or D₂R-selective agonists. RGS10 is highly expressed in microglia, the brain’s resident immune cells. Within the SNc, RGS10 may promote DA neuron survival through the upregulation of prosurvival genes and inhibition of microglial inflammatory factor expression. Thus, RGSs 4, 6, 9, and 10 are critical modulators of cell signaling pathways that promote SNc DA neuron survival and/or proper motor control. Accordingly, these RGS proteins represent novel therapeutic targets for the treatment of PD pathology.

中文翻译：

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RGS 蛋白作为运动功能的关键调节剂及其对帕金森病的影响。

帕金森病 (PD) 是一种破坏性的、主要是非家族性的、与年龄相关的疾病，由黑质致密部 (SNc) 中多巴胺 (DA) 神经元的进行性丧失引起。DA 从这些神经元释放到背侧纹状体对于调节运动至关重要，它们的丢失会导致 PD。不幸的是，SNc 神经变性的潜在机制尚不清楚，目前无法治愈 PD，只能对症治疗。最近，几种 G 蛋白信号转导 (RGS) 蛋白调节剂已成为 PD 发病机制和/或运动功能障碍和运动障碍的关键调节剂：RGS 4、6、9 和 10。纹状体 RGS4 已被证明会加剧 DA 丢失的运动症状通过抑制 M ₄ -autoreceptor-G α _i/o纹状体胆碱能中间神经元中的信号传导。RGS6 和 RGS9 分别是SNc DA 神经元和纹状体中棘神经元中 D ₂ R-G α _i/o信号传导的关键调节器。RGS6 在人和小鼠 SNc DA 神经元中表达，抑制老年小鼠的特征性 PD 标志，包括 SNc DA 神经元丢失、运动缺陷和α-突触核蛋白积累。DA 耗竭后，RGS9（通过抑制中等多刺神经元 D ₂ R 信号）抑制由 L-DOPA 或 D ₂诱导的运动功能障碍R-选择性激动剂。RGS10 在小胶质细胞中高度表达，小胶质细胞是大脑的常驻免疫细胞。在 SNc 中，RGS10 可能通过上调促存活基因和抑制小胶质细胞炎症因子表达来促进 DA 神经元存活。因此，RGS 4、6、9 和 10 是促进 SNc DA 神经元存活和/或适当运动控制的细胞信号通路的关键调节剂。因此，这些 RGS 蛋白代表了治疗 PD 病理的新治疗靶点。